The Berlin patient who has been effectively cured from HIV provides proof of concept for the feasibility of curing HIV infection from the human host. It is likely that at least four factors have contributed to HIV being cured in the Berlin patient: (i) prolonged and durable control of HIV infection prior to bone marrow transplant, (ii) cytotoxic chemotherapy killing the viral reservoir, (iii) being transplanted with CCR5 delta 32 cells which are resistant to infection, and (iv) a broadly effective immune response which was able to eradicate any residual infection. This case has spurred much scientific debate and speculation as to how to make cure of HIV a more generalizable and an achievable outcome. Given the potency of current antiretroviral agents, current efforts are focusing on developing novel ways of killing or purging the viral reservoir (eg SAHA), developing new approaches to generate cells which resist infection (eg Zinc finger nucleases for CCR5) and enhancing the immune control of HIV. TNF related apoptosis inducing factor (TRAIL) is a molecule whose principal function is as an effector of immune surveillance, and it has been implicated in the pathogenesis of both malignancies, as well as viral infections including HIV. Concerning the role of TRAIL in HIV, considerable evidence supports a role for TRAIL dysregulation occurring during HIV infection in vivo, and there is ample evidence that treatment of cells from HIV-infected patients on HAART with exogenous TRAIL, reduces the number of latently infected cells, as measured by undetectable levels of replication competent virus in quantitative co-culture assays. Since TRAIL is expressed by effector cells (i.e., CD8 and/or NK cells) of the immune system, we questioned why TRAIL-dependent natural immune mechanisms do not independently reduce the number of latently infected cells. We found that cells from HIV-infected patients produce a novel splice variant of TRAIL which we call TRAILshort, which antagonizes normal TRAIL signaling. We therefore propose a model whereby the production of TRAILshort by HIV-infected cells prevents these cells from being killed by either CTL or NK cells, and this allows a subset of infected cells to persist. The current research proposal concerns gaining understanding the biology of and developing ways to inhibit this TRAIL splice variant, which we have named TRAILshort (TRAILs). Since we have generated preliminary data which demonstrates that TRAILs blocks HIV induced killing of CD4 T cells, as well as killing induced by CTL and NK cells, we now propose to inhibit TRAILs as a means of increasing the rate at which HIV infected CD4 Tcells die, and thereby contributing to the goal of eradicating HIV infected cells, and a cure for HIV infection. In this regard, we have additional preliminary data indicating that inhibiting TRAILs achieves the goal of increasing killing of HIV infected T-cells, and enhancing both CTL and NK cell killing of target cells.